This invention relates to new cephem compounds and pharmaceutically acceptable salts thereof which are useful as a medicament.
Some cephem compounds have been known as described, for example, in Japanese Kokai H2-134385.
The present invention relates to new cephem compounds and pharmaceutically acceptable salts thereof.
More particularly, it relates to new cephem compounds and pharmaceutically acceptable salts thereof, which have antimicrobial activities, to processes for preparation thereof, to pharmaceutical composition comprising the same and to a method for treating infectious diseases in human being and animals.
Accordingly, one object of the present invention is to provide the cephem compounds and pharmaceutically acceptable salts thereof, which show highly active against a number of pathogenic microorganisms.
Another object of the present invention is to provide processes for the preparation of the cephem compounds and salts thereof.
A further object of the present invention is to provide pharmaceutical compositions comprising, as an active ingredient, said cephem compounds or their pharmaceutically acceptable salts.
Still further object of the present invention is to provide a method for treating infectious diseases caused by pathogenic microorganisms, which comprises administering said cephem compounds to infected human being or animals.
The object cephem compounds of the present invention are novel and can be represented by the following general formula (I): 
wherein R1 is amino or protected amino,
R2 is hydrogen, lower alkyl or hydroxy protective group,
R3 is carboxy or protected carboxy,
R4 is 3-pyridyl, 4-pyridyl or optionally substituted heteromonocyclic group containing two nitrogen atoms as hetero atoms, and which may also contain one oxygen or sulfur atom, and
n is 0, 1 or 2, provided that when R2 is lower alkyl, then n is 1 or 2, and
R4 is optionally substituted heteromonocyclic group containing two nitrogen atoms as hetero atoms,
and which may also contain one oxygen or sulfur atom, or pharmaceutically acceptable salt thereof.
The object compound (I) of the present invention can be prepared by the following processes. 
wherein R1, R2, R3, R4 and n are each as defined above,
Ra2 is hydroxy protective group,
Ra3 is protected carboxy,
R8 is ester moiety of esterified carboxy represented by group of formula: xe2x80x94COOR8,
one of X and Y is acid residue and
the other is mercapto or activated mercapto group, or salt thereof.
Some of the starting compound (II) and (V) are new and the new compounds can be prepared by the following processes, preparations or equivalent processes of those. 
wherein R3, Ra3, R4, n, X and Y are each as defined above,
R6 is amino or protected amino,
Ra6 is protected amino and
R7 is acyl.
Regarding the compounds (I), (Ia), (Ib), (Ic), (Id), (Ie), (III) and (IV), it is to be understood that said compounds include syn isomer(Z), anti isomer(E) and a mixture thereof.
For example, with regard to the object compound (I), syn isomer(Z) means one geometrical isomer having the partial structure represented by the following formula: 
(wherein R1 and R2 are each as defined above), and anti isomer(E) means the other geometrical isomer having the partial structure represented by the following formula: 
(wherein R1, R2 and Z are each as defined above), and all of such geometrical isomers and mixture thereof are included within the scope of this invention.
In the present specification and claim, the partial structure of these geometrical isomers and mixture thereof are represented for convenient sake by the following formula: 
(wherein R1, R2 and Z are each as defined above).
It is to be noted that the compound (I) and the other compounds may include one or more stereoisomers due to asymmetric carbon atom(s), and all of such isomers and mixture thereof are included within the scope of this invention.
It is also to be noted that the solvate of the compound (I) [e.g. hydrate, lower alcohol solvate (e.g. methanol solvate, ethanol solvate, isopropanol solvate, etc), etc.] and any form of the crystal of the compound (I) are included within the present invention.
In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions, which the present invention include within the scope thereof, are explained in detail as follows.
The term xe2x80x9clowerxe2x80x9d is intended to mean 1 to 6 carbon atom(s) unless otherwise indicated.
Suitable xe2x80x9clower alkylxe2x80x9d may include straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, and the like, in which more preferred one may be C1-C4 alkyl and the most preferred one may be methyl, ethyl or propyl.
Suitable xe2x80x9cprotected aminoxe2x80x9d group may include an amino group substituted by a conventional amino protective group which is easily removable such as acyl as defined below, such as organic silyl group which may have suitable substituent(s) (e.g., mono-, di- or tri(lower)alkylsilyl, etc.), such as ar(lower)alkyl which may have suitable substituent(s) (e.g. benzyl, trityl, p-nitrobenzyl, etc.) or the like.
Suitable xe2x80x9cacylxe2x80x9d may include carbamoyl, aliphatic acyl group and acyl group containing an aromatic or heterocyclic ring. The aliphatic acyl may include saturated or unsaturated, acyclic or cyclic ones, such as alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.); lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tertiarybutoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.); lower alkanesulfonyl (e.g. mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, etc.) and the like. The acyl group containing aromatic or heterocyclic ring may include arenesulfonyl (e.g. benzenesulfonyl, tosyl, etc.); aroyl (e.g. benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, indancarbonyl, etc.); ar(lower)alkanoyl (e.g. phenylacetyl, phenylpropionyl, etc.); ar(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc.), and the like. The acyl moiety as stated above may have suitable substituent(s) such as halogen (e.g. chlorine, bromine, iodine or fluorine), lower alkyl as defined above, or the like.
Suitable xe2x80x9cprotected carboxyxe2x80x9d may include an esterified carboxy and the like. Suitable example of said ester may be the ones such as lower alkyl ester (e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester, etc.); lower alkenyl ester (e.g., vinyl ester, allyl ester, etc.); lower alkynyl ester (e.g., ethynyl ester, propynyl ester, etc.); lower alkoxyalkyl ester (e.g., methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester, 1-methoxyethyl ester, 1-ethoxyethyl ester, etc.); lower alkylthioalkyl ester (e.g., methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester, isopropylthiomethyl ester, etc.); mono(or di or tri)halo(lower)alkyl ester (e.g. 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.); lower alkanoyloxy(lower)alkyl ester (e.g., acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1-acetoxyethyl ester, 2-acetoxyethyl ester, 1-propionyloxyethyl ester, etc.); cyclo(lower)alkylcarbonyloxy(lower)alkyl ester (e.g., 1-(cyclohexylcarbonyloxy)ethyl ester, etc.); lower alkoxycarbonyloxy(lower)alkyl ester (e.g., methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, 1-(or 2-)[methoxycarbonyloxy]ethyl ester, 1-(or 2-)[ethoxycarbonyloxy]ethyl ester, 1-(or 2-)[propoxycarbonyloxy]ethyl ester, 1-(or 2-)[isopropoxycarbonyloxy]ethyl ester, etc.); cyclo(lower)alkyloxycarbonyloxy(lower)alkyl ester (e.g., 1-(cyclohexyloxycarbonyloxy)ethyl ester, etc.); lower alkanesulfonyl(lower)alkyl ester (e.g. mesylmethyl ester, 2-mesylethyl ester etc.); ar(lower)alkyl ester, for example, phenyl(lower)alkyl ester which may have one or more suitable substituent(s) (e.g., benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-t-butylbenzyl ester, etc.); aryl ester which may have one or more suitable substituent(s) such as substituted or unsubstituted phenyl ester (e.g., phenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, 4-chlorophenyl ester, 4-methoxyphenyl ester, etc.); tri(lower)alkyl silyl ester; lower alkylthioester (e.g. methylthioester, ethylthioester, etc.) and the like.
Suitable xe2x80x9chydroxy protective groupxe2x80x9d may include a conventional one which is easily removable such as acyl as mentioned above, cyclo(lower)alkenyl (preferable example of cyclo(lower)alkenyl is cyclo(C3-8)alkenyl such as cyclopentenyl or cyclohexenyl, etc.), phenyl(lower)alkyl which may have one or more suitable substituent(s) (e.g., benzyl, 4-methoxybenzyl, trityl, etc.), substituted silyl (e.g., trimethylsilyl, t-butyldimethylsilyl, etc.), tetrahydropyranyl and the like.
Suitable xe2x80x9carylxe2x80x9d may include phenyl, naphthyl and the like.
Suitable xe2x80x9cheteromonocyclic group containing two nitrogen atoms as hetero atoms, which may also contain one or more oxygen or sulfur atomsxe2x80x9d may include saturated or unsaturated, aromatic or non-aromatic 3 to 8-membered heteromonocyclic group containing two nitrogen atoms which may have one or more substituents. The heteromonocyclic group for R4 can be attached to the adjacent partial structure-(CH2)n at the carbon atom or the hetero atom in the heteromonocyclic ring, more preferably attached to the adjacent partial structure-(CH2)n at the carbon atom in the heteromonocyclic ring.
Preferable example of heteromonocyclic group is
(1) 5, 6 or 7 membered unsaturated heteromonocyclic ring containing 2 nitrogen atoms as hetero atoms such as pyrazole, pyrazoline, imidazole, imidazoline, pyrimidine or its partially hydrogenated compound, pyridazine or its partially hydrogenated compound, pyrazine or its partially hydrogenated compound,
(2) 5, 6 or 7 membered heteromonocyclic ring containing 2 nitrogen atoms and more than 1 sulfur atom as hetero atoms such as 1,2,5-thiadiazole, 1,2,4-thiadiazole, 1,2,3-thiadiazole, 6H-1,2,5-thiadiazine or their hydrogenated compound,
(3) 5, 6 or 7 membered heteromonocyclic ring containing 2 nitrogen atoms and more than 1 oxygen atom as hetero atoms as hetero atoms such as 1,2,3-oxadiazole, 1,2,5-oxadiazole 1,2,4-oxadiazole, 6H-1,2,5-oxadiazine or their hydrogenated compounds.
(4) saturated 5, 6 or 7 membered heteromonocyclic ring containing 2 nitrogen atoms as hetero atoms such as pyrazolidine, imidazolidine, piperazine, 1,3-diazacyclohexane, 1,2-diazacyclohexane.
The heteromonocyclic group for may have one to four, same and different, suitable substituent(s) such as lower alkyl as exemplified before; lower alkoxy (e.g. methoxy, ethoxy, propoxy, etc.); lower alkylthio (e.g. methylthio, ethylthio, etc.); lower alkylamino (e.g. methylamino, ethylamino, etc.); cyclo(lower)alkyl (e.g. cyclopentyl, cyclohexyl, etc.); cyclo(lower)alkenyl (e.g. cyclohexeny, cyclohexadienyl, etc.); halogen; amino; protected amino as exemplified before; protected hydroxy which has a hydroxy protective group as exemplified before; cyano; nitro; carboxy; hydroxy(lower)alkyl (e.g. hydroxymethyl, 2-hydroxyethyl, etc.); amino(lower)alkyl (e.g. aminomethyl, aminoethyl, etc.); carbamoyloxy; and the like.
More preferable xe2x80x9coptionally substituted heteromonocyclic group containing two nitrogen atoms as hetero atoms, which may also contain one oxygen or sulfur atomxe2x80x9d may include 5 or 6 membered, 4-methyl-1,2,3-thiadiazol-5-yl, pyrazol-4-yl, 1-methylpyrazol-4-yl, 1,2,5-thiadiazol-3-yl, 2-methyl-1,3,4-thiadiazol-5-yl, 3-methyl-1,2,4-thiaziazol-5-yl, imidazol-2-yl, 2-methyl-1,3,4-oxadiazol-5-yl, pyradin-2-yl, pyrimidin-4-yl, pyridazin-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl and the like.
Suitable xe2x80x9cacid residuexe2x80x9d may include halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), acyloxy in which the acyl moiety can be referred to one as aforementioned and the like. More preferable acyloxy is sulfonyloxy (e.g., methanesulfonyloxy, benzenesulfonyloxy, tosyloxy, etc.), lower alkanoyloxy (e.g., acetyloxy, propionyloxy, etc.), etc.
Suitable salt of mercapto group or activated mercapto group of the compound (V) may include a metal salt such as an alkali metal salt (e.g., sodium salt, potassium salt, etc.) an alkaline earth metal salt (e.g., magnesium salt, etc.), aluminum salt, an acylated thiol and the like.
Suitable xe2x80x9cacyl moietyxe2x80x9d in the term xe2x80x9cacylated thiolxe2x80x9d may include aliphatic acyl group and acyl group containing an aromatic or heterocyclic ring. And suitable examples of the said acyl may be lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.); aroyl (e.g. benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, indancarbonyl, etc.); ar(lower)alkanoyl (e.g. phenylacetyl, phenylpropionyl, etc.); ar(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc.), and the like. The acyl moiety as stated above may have suitable substituent(s) such as halogen (e.g. chloride, bromine, iodine or fluorine), lower alkyl as defined above, or the like.
Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic pharmaceutically acceptable salts and include a salt with a base or an acid addition salt, for example an inorganic base salt [a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt etc.], an organic base salt [e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,Nxe2x80x2-dibenzylethylenediamine salt, etc.], an organic acid salt [e.g. formate, acetate trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.], an inorganic acid salt [e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.], a salt with an amino acid [e.g. arginine salt, aspartic acid salt, glutamic acid salt, etc.], and the like.